Oxidative stress in the brain is involved in the pathogenesis of heart failure.

摘要

Increased angiotensin II (AngII) signaling in the brain is thought to be involved in the pathogenesis of heart failure (HF) following myocardial infarction (MI). Recent work in our laboratory demonstrated superoxide mediates central AngII signaling. In this study, we tested the hypothesis that increased oxidative stress in cardiovascular control regions of the brain plays a critical role in the pathogenesis of HF. Ligation of the left coronary artery was used to induce a large MI and subsequent HF in adult C57BL/6 mice. MI mice demonstrated an increase in central AngII signaling and AT1 receptor down-regulation within the subfornical organ (SFO) and paraventricular nucleus (PVN), two key cardiovascular control regions. In addition, dihydroethidium staining revealed an MI-induced increase in superoxide levels in the SFO. Intracerebroventricular (ICV) injection of an adenoviral vector encoding Cu/Zn superoxide dismutase (Ad-Cu/ZnSOD) abolished the oxidative stress in the SFO. Furthermore, Fos immunohistochemistry, a marker of chronic neuronal activation, revealed that ICV Ad-CU/ZnSOD also attenuated the MI-induced increase in Fos-positive neurons in the PVN and supraoptic nucleus. MI mice treated centrally with Ad-Cu/ZnSOD also revealed a decrease in sympathetic tone, as demonstrated by significantly attenuated falls in heart rate and mean arterial pressure in response to ganglionic blockade with hexamethonium and decreased urinary norepinephrine levels, compared to MI mice treated with the control vector. Moreover, ICV administration of Ad-Cu/ZnSOD decreased the rate of ventricular rupture, inhibited cardiomyocyte apoptosis, and improved cardiac performance following MI. To confirm our findings using a pharmacologic approach, we examined the effect of administration of the superoxide dismutase mimetic, Tempol, in the drinking water (1mM) on cardiac performance following MI. Tempol produced effects similar to those observed with ICV Ad-Cu/ZnSOD, including improved survival, decreased urinary norepinephrine levels, inhibition of cardiomyocyte apoptosis, and improved cardiac function following MI. These results suggest that oxidative stress in the brain plays a key role in the neurohumoral activation following MI, and underscore the promise antioxidant therapy holds for the treatment of HF.